Atherosclerotic coronary artery disease is a major cause of death and morbidity as well as a significant drain on healthcare resources in the western world. It is well known that cholesteryl esters are a major risk factor for atherosclerotic lesions, and also a major storage form in the arterial wall cells of the cholesterol.
Regulations of cholesterol homeostasis of human and animal bodies involve regulations of dietary cholesterol and regulations of biosynthesis of cholesterol, biosynthesis of bile acid and metabolism of plasma lipoprotein containing cholesterol. The cholesterol from food and bile origin is absorbed from the intestine, and enters the circulation as a component of chylomicrons. In another aspect, the cholesterol is biosynesized and metabolized by the liver, and therefore, it is the major determinant of plasma cholesterol levels. The liver is the site for synthesis and secretion of the very low density lipoprotein (VLDL), and then the VLDL is metabolized to the low density lipoprotein (LDL) in circulation. LDL is a major form of cholesterol with lipoprotein in plasma, and its increased concentration associates with the increase of atherosclerosis. No matter by what means, if the intestinal cholesterol absorption is reduced, less cholesterol will be delivered to the liver, which results in a reduction in the production of hepatic lipoprotein (VLDL), as well as an increase in hepatic clearance of plasma cholesterol.
At present, many clinical studies have clearly demonstrated that increase of the total serum cholesterol level is one of the major risk factors for coronary artery disease. The higher the level of the total serum cholesterol is, the greater the risk is and the earlier the time is for the occurrence of the atherosclerosis. The total serum cholesterol is reduced by 1%, the risk of the occurrence of coronary artery disease can be reduced by 2%. Therefore, inhibition of the formation of cholesteryl esters and reduction of the serum cholesterol may inhibit the development of formation of atherosclerotic lesions, reduce the accumulation of cholesteryl esters in arterial walls and prevent the intestinal absorption of dietary cholesterol.
Even with the current diverse range of therapeutic agents, such as statins, e.g. simvastatin and fluvastatin, bile acid binder, fibrates, niacin analogues, significant proportion of the hypercholesterolaemic population is unable to reach target cholesterol levels, or drug interactions or drug safety preclude the long term use needed to reach the target levels. Therefore, there is still a need to develop additional agents that are more efficacious and are better tolerated.
Compounds possessing such cholesterol absorption inhibitory activity have been described, see for instance the compounds described in WO 93/02048, WO 94/17038, WO 95/08532, WO 95/26334, WO 95/35277, WO 96/16037, WO 96/19450, WO 97/16455, WO 02/50027, WO 02/50060, WO 02/50068, WO 02/50090, WO 02/66464, WO 04/000803, WO 04/000804, WO04/000805, U.S. Pat. No. 5,756,470, U.S. Pat. No. 5,767,115, and US RE37721. Most of them reported the azetidinone compounds for reduction of cholesterol and/or inhibitory of the formation of lesions in artery walls of mammals.
The present invention is based on the above discovery of surprising inhibition of 2-azetidinone derivatives on cholesterol absorption. The present invention synthesizes and structurally modifies these azetidinone compounds, to look for azetidinone compounds with more efficacious inhibitory effect on cholesterol. The compounds of the present invention are not disclosed in any of the above applications.
The present invention further relates to the use of the azetidinone compounds of the present invention to reduce serum cholesterol levels.